Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components

Ogura, Masato; Yamaki, Junko; Homma, Miwako K.; Homma, Yoshimi

doi:10.1042/bj20120509

Cited by 82 publications

(96 citation statements)

References 41 publications

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“…are thus consistent with a model in which TRAP1 regulates the previously reported ability of mitochondrial c-Src to stimulate oxidative phosphorylation (14,15). Reduced/absent TRAP1 expression also correlates with increased cell motility/invasiveness that is sensitive to c-Src inhibition and ROS buffering strategies.…”

supporting

confidence: 75%

“…Miyazaki et al first reported that c-Src is located within mitochondria and affects energy metabolism by phosphorylating complex IV (14). Later studies confirmed that c-Src is present in the inner mitochondrial membrane/matrix (15). Although the mechanism by which TRAP1 regulates mitochondrial c-Src is not yet clarified, the cytosolic c-Src-HSP90 interaction provides a model to address this question.…”

Section: Discussionmentioning

confidence: 99%

“…Based on these data and on previous reports that mitochondrial c-Src stimulates complex IV activity and enhances oxidative phosphorylation (14,15), we speculated that the effect of TRAP1 on mitochondrial respiration may depend on its regulation of mitochondrial c-Src. To investigate this possibility, we confirmed that c-Src overexpression significantly increased the OCR of isolated HeLa cell mitochondria, but simultaneous overexpression of TRAP1 partially reversed this effect (Fig.…”

Section: Trap1 and Mitochondrial C-src Have Opposing Effects Onmentioning

confidence: 99%

“…Plasmid expressing WT c-Src was purchased from Upstate Biotechnology. Plasmids expressing mitochondrially targeted c-Src constructs were kind gifts of Y. Homma (Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima, Japan) (15). MAFs were transiently transfected with TRAP1-GFP or empty-GFP plasmid using an Amaxa Nucleofector (Lonza), according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Unexpectedly, we found TRAP1 to be tyrosine phosphorylated (Fig. 3A, Left), which caused us to examine c-Src, a kinase reported to be present in mitochondria (14,15,(30)(31)(32)(33). We probed TRAP1 immunoprecipitates for c-Src association and we identified c-Src as a TRAP1-interacting protein in HCT116 cells (Fig.…”

Section: Trap1 Interacts With Mitochondrial C-src and Suppresses Its mentioning

confidence: 99%

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Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Yoshida

Tsutsumi²,

Mühlebach

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

229

272

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TRAP1 (TNF receptor-associated protein), a member of the HSP90 chaperone family, is found predominantly in mitochondria. TRAP1 is broadly considered to be an anticancer molecular target. However, current inhibitors cannot distinguish between HSP90 and TRAP1, making their utility as probes of TRAP1-specific function questionable. Some cancers express less TRAP1 than do their normal tissue counterparts, suggesting that TRAP1 function in mitochondria of normal and transformed cells is more complex than previously appreciated. We have used TRAP1-null cells and transient TRAP1 silencing/overexpression to show that TRAP1 regulates a metabolic switch between oxidative phosphorylation and aerobic glycolysis in immortalized mouse fibroblasts and in human tumor cells. TRAP1-deficiency promotes an increase in mitochondrial respiration and fatty acid oxidation, and in cellular accumulation of tricarboxylic acid cycle intermediates, ATP and reactive oxygen species. At the same time, glucose metabolism is suppressed. TRAP1-deficient cells also display strikingly enhanced invasiveness. TRAP1 interaction with and regulation of mitochondrial c-Src provide a mechanistic basis for these phenotypes. Taken together with the observation that TRAP1 expression is inversely correlated with tumor grade in several cancers, these data suggest that, in some settings, this mitochondrial molecular chaperone may act as a tumor suppressor.M olecular chaperones help to maintain cellular homeostasis.The heat-shock protein 90 (HSP90) family of molecular chaperones is highly conserved from bacteria to mammals. HSP90 itself is an essential molecular chaperone found in the cytoplasm and nucleus of all eukaryotic cells (1, 2). In multicellular eukaryotes, the HSP90 family includes the mitochondrial chaperone TRAP1 (TNF receptor-associated protein), which shares 50% sequence similarity with HSP90. Although TRAP1 binds and hydrolyzes ATP in an analogous manner to HSP90 (3), its cellular function is less well understood. Thus, although many HSP90-dependent proteins ("clients") and interacting cochaperones have been described (www.picard.ch/downloads/Hsp90interactors.pdf), the validated list of TRAP1-dependent clients is quite small and TRAP1-interacting cochaperones, if they exist, have yet to be identified (4).Several studies have suggested that TRAP1 plays a cytoprotective role by buffering reactive oxygen species (ROS)-mediated oxidative stress (5, 6), and others have reported that TRAP1 overexpression attenuates ROS production (7). The antioxidant properties of TRAP1, together with its reported ability to regulate opening of the mitochondrial permeability transition pore (8, 9), may contribute to its antiapoptotic activity (4). For these reasons, TRAP1 has been proposed as an anticancer molecular target, and first-generation inhibitors have shown some anticancer activity in preclinical models (10). However, these inhibitors do not distinguish between HSP90 and TRAP1 (11), and TRAP1 expression in cancer is variable but HSP90 comprises as much as 5% of...

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supporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Trap1 and Mitochondrial C-src Have Opposing Effects Onmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Trap1 Interacts With Mitochondrial C-src and Suppresses Its mentioning

confidence: 99%

See 3 more Smart Citations

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Yoshida

Tsutsumi²,

Mühlebach

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

229

272

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The roles of molecular chaperones in regulating cell metabolism

Binder

Pedley

2023

FEBS Letters

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Fluctuations in nutrient and biomass availability, often as a result of disease, impart metabolic challenges that must be overcome in order to sustain cell survival and promote proliferation. Cells adapt to these environmental changes and stresses by adjusting their metabolic networks through a series of regulatory mechanisms. Our understanding of these rewiring events has largely been focused on those genetic transformations that alter protein expression and the biochemical mechanisms that change protein behavior, such as post‐translational modifications and metabolite‐based allosteric modulators. Mounting evidence suggests that a class of proteome surveillance proteins called molecular chaperones also can influence metabolic processes. Here, we summarize several ways the Hsp90 and Hsp70 chaperone families act on human metabolic enzymes and their supramolecular assemblies to change enzymatic activities and metabolite flux. We further highlight how these chaperones can assist in the translocation and degradation of metabolic enzymes. Collectively, these studies provide a new view for how metabolic processes are regulated to meet cellular demand and inspire new avenues for therapeutic intervention.

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The Changes of Mitochondria during Aging and Regeneration

Li,

Qin,

Gong

2024

Advanced Biology

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Aging and regeneration are opposite cellular processes. Aging refers to progressive dysfunction in most cells and tissues, and regeneration refers to the replacement of damaged or dysfunctional cells or tissues with existing adult or somatic stem cells. Various studies have shown that aging is accompanied by decreased regenerative abilities, indicating a link between them. The performance of any cellular process needs to be supported by the energy that is majorly produced by mitochondria. Thus, mitochondria may be a link between aging and regeneration. It should be interesting to discuss how mitochondria behave during aging and regeneration. The changes of mitochondria in aging and regeneration discussed in this review can provide a timely and necessary study of the causal roles of mitochondrial homeostasis in longevity and health.

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Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components

Cited by 82 publications

References 41 publications

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis

The roles of molecular chaperones in regulating cell metabolism

The Changes of Mitochondria during Aging and Regeneration

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